Mutations in the DJ-1 gene are a rare genetic cause of autosomal recessive Parkinson's disease (PD). The DJ-1 protein is either absent or appears to be functionally inactive in the families in which mutation have been identified. Thus, mutations in the DJ-1 gene probably cause PD through a loss of function. It is difficult at this juncture to fully appreciate how mutations in the DJ-1 gene cause PD, as its function is largely unknown. DJ-1 was identified as a hydroperoxide-responsive protein that becomes more acidic following oxidative stress suggesting that it may function as an antioxidant protein. Furthermore, DJ-1 is sumoylated through binding to the SUMO-1 ligase, PIAS, suggesting that it might be involved in the regulation of transcription. Other putative functions of DJ-1 have been raised, but how a loss of function of DJ-1 leads to loss of DA neurons and PD awaits further study. We propose to generate and characterize DJ-1 knockout mice to formally test the hypothesis that the absence of DJ-1 function is the cause of PD due to DJ-1 mutations. Accordingly experiments are proposed to further characterize the role of DJ-1 in the pathogenesis of PD. In Specific Aim #1 we will develop and characterize DJ-1 knockout mice. In Specific Aim #2 we will evaluate the sensitivity of DJ-1 knockouts to environmental toxins including MPTP-induced dopaminergic cell death. In Specific Aim #3 we will determine whether DJ-1 interacts with parkin by evaluating the effect of crossing DJ-1 knockout mice with parkin knockout mice. Development and characterization of DJ-1 knockouts, understanding the relationship of DJ-1 and parkin in the pathogenesis of PD may provide insight into the molecular mechanisms by which these gene products induce neuronal damage and may provide novel therapeutics and targets to prevent the toxic effects of these familial associated genes in the degenerative process of PD.